RESUMO
Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n=7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P<0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r=0.76; P=0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n=11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 14/genética , Impressão Genômica , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Pais , Dissomia Uniparental/genética , Metilação de DNA , Exoma/genética , Heterozigoto , Homozigoto , Humanos , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , PrognósticoAssuntos
Análise Mutacional de DNA/métodos , Proteínas de Ligação a DNA/genética , DNA/sangue , DNA/genética , Leucemia/genética , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Sequência de Bases , Estudos de Coortes , Dioxigenases , Feminino , Seguimentos , Humanos , Masculino , Dados de Sequência Molecular , PrognósticoRESUMO
We examined the reproductive success of 48 adult brown trout (Salmo trutta L.) which were allowed to reproduce in a stream that was controlled for the absence of other trout. Parentage analyses based on 11 microsatellites permitted us to infer reproductive success and mate choice preferences in situ. We found that pairs with intermediate major histocompatibility complex (MHC) dissimilarity mated more often than expected by chance. It appears that female choice was the driving force behind this observation because, compared with other individuals, males with intermediate MHC dissimilarity produced a larger proportion of offspring, whereas female reproductive output did not show this pattern. Hence, rather than seeking mates with maximal MHC dissimilarity, as found in several species, brown trout seemed to prefer mates of intermediate MHC difference, thus supporting an optimality-based model for MHC-dependent mate choice.